Christopher R. Frei

Association of Azithromycin With Mortality and Cardiovascular Events Among Older Patients Hospitalized With Pneumonia

IMPORTANCE Although clinical practice guidelines recommend combination therapy with macrolides, including azithromycin, as first-line therapy for patients hospitalized with pneumonia, recent research suggests that azithromycin may be associated with increased cardiovascular events. OBJECTIVE To examine the association of azithromycin use with all-cause mortality and cardiovascular events for patients hospitalized with pneumonia. DESIGN Retrospective cohort study comparing older patients hospitalized with pneumonia from fiscal years 2002 through 2012 prescribed azithromycin therapy and patients receiving other guideline-concordant antibiotic therapy. SETTING This study was conducted using national Department of Veterans Affairs administrative data of patients hospitalized at any Veterans Administration acute care hospital. PARTICIPANTS Patients were included if they were aged 65 years or older, were hospitalized with pneumonia, and received antibiotic therapy concordant with national clinical practice guidelines. MAIN OUTCOMES AND MEASURES Outcomes included 30- and 90-day all-cause mortality and 90-day cardiac arrhythmias, heart failure, myocardial infarction, and any cardiac event. Propensity score matching was used to control for the possible effects of known confounders with conditional logistic regression. RESULTS Of 73,690 patients from 118 hospitals identified, propensity-matched groups were composed of 31,863 patients exposed to azithromycin and 31,863 matched patients who were not exposed. There were no significant differences in potential confounders between groups after matching. Ninety-day mortality was significantly lower in those who received azithromycin (exposed, 17.4%, vs unexposed, 22.3%; odds ratio [OR], 0.73; 95% CI, 0.70-0.76). However, we found significantly increased odds of myocardial infarction (5.1% vs 4.4%; OR, 1.17; 95% CI, 1.08-1.25) but not any cardiac event (43.0% vs 42.7%; OR, 1.01; 95% CI, 0.98-1.05), cardiac arrhythmias (25.8% vs 26.0%; OR, 0.99; 95% CI, 0.95-1.02), or heart failure (26.3% vs 26.2%; OR, 1.01; 95% CI, 0.97-1.04). CONCLUSIONS AND RELEVANCE Among older patients hospitalized with pneumonia, treatment that included azithromycin compared with other antibiotics was associated with a lower risk of 90-day mortality and a smaller increased risk of myocardial infarction. These findings are consistent with a net benefit associated with azithromycin use.

Antimicrobial breakpoints for Gram-negative aerobic bacteria based on pharmacokinetic–pharmacodynamic models with Monte Carlo simulation

OBJECTIVES This study describes a comprehensive programme designed to develop pharmacokinetic-pharmacodynamic (PK-PD) breakpoints for numerous antimicrobial classes against key gram-negative aerobic bacteria. METHODS A 10,000 subject Monte Carlo simulation was constructed for 13 antimicrobials (21 dosing regimens). Published pharmacokinetic data and protein binding were varied according to log-normal and uniform distributions. MICs were fixed at single values from 0.03 to 64 mg/L. The PK-PD susceptible breakpoint was defined as the MIC at which the probability of target attainment was > or = 90%. PK-PD, CLSI and European Committee on Antimicrobial Susceptibility Testing breakpoints were applied to MICs from the 2005 worldwide Meropenem Yearly Susceptibility Test Information Collection database to evaluate the impact of breakpoint discrepancies. RESULTS PK-PD breakpoints were within one dilution of the CLSI and European breakpoints for all antimicrobials tested--with a few exceptions. When discrepancies were noted, the PK-PD breakpoint was lower than the CLSI breakpoint [ceftriaxone (0.5 versus 8 mg/L), ertapenem (0.25 versus 2 mg/L), ciprofloxacin (0.125 versus 1 mg/L) and levofloxacin (0.25-0.5 versus 2 mg/L)] and higher than the European breakpoint [ceftazidime (4-8 versus 1 mg/L), aztreonam (4-8 versus 1 mg/L), although ciprofloxacin was an exception to this pattern (0.125 versus 0.5-1 mg/L)]. For Enterobacteriaceae, breakpoint discrepancies resulted in modest (< or = 10%) differences in the percentages susceptible. In contrast, large (> 15%) discrepancies were noted for Pseudomonas aeruginosa and Acinetobacter baumannii. CONCLUSIONS Breakpoint agreement exists for imipenem, meropenem and the aminoglycosides. In contrast, discrepancies exist for piperacillin/tazobactam, cephalosporins, ertapenem, aztreonam and the fluoroquinolones. These discrepancies are most pronounced for P. aeruginosa and A. baumannii.

Guideline-Concordant Therapy and Outcomes in Healthcare-Associated Pneumonia

Healthcare-associated pneumonia (HCAP) guidelines were first proposed in 2005 but have not yet been validated. The objective of this study was to compare 30-day mortality in HCAP patients treated with either guideline-concordant (GC)-HCAP therapy or GC community-acquired pneumonia (CAP) therapy. We performed a population-based cohort study of >150 hospitals in the US Veterans Health Administration. Patients were included if they had one or more HCAP risk factors and received antibiotic therapy within 48 h of admission. Critically ill patients were excluded. Independent risk factors for 30-day mortality were determined in a generalised linear mixed-effect model, with admitting hospital as a random effect. Propensity scores for the probability of receiving GC-HCAP therapy were calculated and incorporated into a second logistic regression model. A total of 15,071 patients met study criteria and received GC-HCAP therapy (8.0%), GC-CAP therapy (75.7%) or non-GC therapy (16.3%). The strongest predictors of 30-day mortality were recent hospital admission (OR 2.49, 95% CI 2.12–2.94) and GC-HCAP therapy (OR 2.18, 95% CI 1.86–2.55). GC-HCAP therapy remained an independent risk factor for 30-day mortality (OR 2.12, 95% CI 1.82–2.48) in the propensity score analysis. In nonsevere HCAP patients, GC-HCAP therapy is not associated with improved survival compared with GC-CAP therapy.

The rise in Clostridium difficile infection incidence among hospitalized adults in the United States: 2001-2010

BACKGROUND Clostridium difficile infection (CDI) incidence is a growing concern. This study provides national estimates of CDI over 10 years and identifies trends in mortality and hospital length of stay (LOS) among hospitalized adults with CDI. METHODS We conducted a retrospective analysis of the US National Hospital Discharge Surveys from 2001-2010. Eligible cases included adults aged ≥ 18 years discharged from a hospital with an ICD-9-CM diagnosis code for CDI (008.45). Data weights were used to derive national estimates. CDI incidence rates were depicted as CDI discharges per 1,000 total adult discharges. RESULTS These data represent 2.2 million adult hospital discharges for CDI over the study period. CDI incidence increased from 4.5 CDI discharges per 1,000 total adult discharges in 2001 to 8.2 CDI discharges per 1,000 total adult discharges in 2010. The overall in-hospital mortality rate was 7.1% for the study period. Mortality increased slightly over the study period, from 6.6% in 2001 to 7.2% in 2010. Median hospital LOS was 8 days (interquartile range, 4-14 days), and remained stable over the study period. CONCLUSIONS The incidence of CDI among hospitalized adults in the United States nearly doubled from 2001-2010. Furthermore, there is little evidence of improvement in patient mortality or hospital LOS.

Guideline-Concordant Antibiotic Use and Survival Among Patients With Community-Acquired Pneumonia Admitted to the Intensive Care Unit

OBJECTIVE This study evaluated the survival benefit of US community-acquired pneumonia (CAP) practice guidelines in the intensive care unit (ICU) setting. METHODS We conducted a retrospective cohort study of adult patients with CAP who were admitted to 5 community hospital ICUs between November 1, 1999, and April 30, 2000. The guidelines for antibiotic prescriptions were the 2007 Infectious Diseases Society of America/American Thoracic Society guidelines. Guideline-concordant antimicrobial therapy was defined as a beta-lactam plus fluoroquinolone or macrolide, antipseudomonal beta-lactam plus fluoroquinolone, or antipseudomonal beta-lactam plus aminoglycoside plus fluoroquinolone or macrolide. Patients with a documented beta-lactam allergy were considered to have received guideline-concordant therapy if they received a fluoroquinolone with or without clindamycin, or aztreonam plus fluoroquinolone with or without aminoglycoside. All other antibiotic regimens were considered to be guideline discordant. Time to clinical stability, time to oral antibiotics, length of hospital stay, and in-hospital mortality were evaluated with regression models that included the outcome as the dependent variable, guideline-concordant antibiotic therapy as the independent variable, and the Pneumonia Severity Index (PSI) score and facility as covariates. RESULTS The median age of the 129 patients included in the study was 71 years (interquartile range, 60-79 years). Sixty-two of 129 patients (48%) were male. Comorbidities included liver dysfunction (7 patients [5%]), heart failure (62 [48%]), renal dysfunction (39 [30%]), cerebrovascular disease (21 [16%]), and cancer (14 [11%]). The median (25th-75th percentile) PSI score was 119 (98-142), and overall mortality was 19% (25 patients). Patient demographics were similar between groups. Fifty-three patients (41%) received guideline-endorsed therapies. Guideline-discordant therapy was associated with an increase in inpatient mortality (25% vs 11%; odds ratio = 2.99 [95% CI, 1.08-9.54]). Receipt of guideline-concordant antibiotics was not associated with reductions in time to clinical stability, time to oral antibiotics, or length of hospital stay when patients who died were excluded from the analysis. CONCLUSION Guideline-concordant empiric antibiotic therapy was associated with improved survival among these patients with CAP who were admitted to 5 ICUs.

Population-Based Study of Statins, Angiotensin II Receptor Blockers, and Angiotensin-Converting Enzyme Inhibitors on Pneumonia-Related Outcomes

BACKGROUND Studies suggest that statins and angiotensin-converting enzyme (ACE) inhibitors might be beneficial for the treatment of infections. Our purpose was to examine the association of statin, ACE inhibitor, and angiotensin II receptor blocker (ARB) use with pneumonia-related outcomes. METHODS We conducted a retrospective cohort study using Department of Veterans Affairs data of patients aged ≥ 65 years hospitalized with pneumonia. We performed propensity-score matching for 3 medication classes simultaneously. RESULTS Of 50119 potentially eligible patients, we matched 11498 cases with 11498 controls. Mortality at 30 days was 13%; 34% used statins, 30% ACE inhibitors, and 4% ARBs. In adjusted models, prior statin use was associated with decreased mortality (odds ratio [OR], 0.74; 95% confidence interval [CI], .68-.82) and mechanical ventilation (OR, 0.81; 95% CI, .70-.94), and inpatient use with decreased mortality (OR, 0.68; 95% CI, .59-.78) and mechanical ventilation (OR, 0.68; 95% CI, .60-.90). Prior (OR, 0.88; 95% CI, .80-.97) and inpatient (OR, 0.58; 95% CI, .48-.69) ACE inhibitor use was associated with decreased mortality. Prior (OR, 0.73; 95% CI, .58-.92) and inpatient ARB use (OR, 0.47; 95% CI, .30-.72) was only associated with decreased mortality. Use of all 3 medications was associated with reduced length of stay. CONCLUSIONS Statins, and to a lesser extent ACE inhibitors and ARBs, are associated with improved pneumonia-related outcomes. Prospective cohort and randomized controlled trials are needed to examine potential mechanisms of action and whether acute initiation at the time of presentation with these infections is beneficial.

Association of Statin Use With Cataracts: A Propensity Score–Matched Analysis

IMPORTANCE Cataracts are a main cause of low vision; with the growing elderly population, the incidence of cataracts is likely to increase. Investigators have previously hypothesized that statin antioxidant effects may slow the natural aging process of the lens. OBJECTIVE To compare the risks for development of cataracts between statin users and nonusers. DESIGN A propensity score-matched cohort analysis using retrospective data from October 1, 2003, to March 1, 2010. A propensity score-matched cohort of statin users and nonusers was created using 44 variables. SETTING Database of a military health care system. PARTICIPANTS Based on medication fills during fiscal year 2005, patients were divided into 2 groups: (1) statin users (received at least a 90-day supply of statin) and (2) nonusers (never received a statin throughout the study). Among 46,249 patients meeting study criteria, we identified 13,626 statin users and 32,623 nonusers. EXPOSURE Use of statin therapy for more than 90 days. MAIN OUTCOMES AND MEASURES Primary analysis examined the risks for cataract in the propensity score-matched cohort. Secondary analyses examined the risks for cataract in patients with no comorbidities according to the Charlson Comorbidity Index (patients with no Charlson comorbidity). A sensitivity analysis was conducted to repeat the secondary analysis in patients taking statins for durations of 2, 4, and 6 years. RESULTS For our primary analysis, we matched 6972 pairs of statin users and nonusers. The risk for cataract was higher among statin users in comparison with nonusers in the propensity score-matched cohort (odds ratio, 1.09; 95% CI, 1.02-1.17). In secondary analyses, after adjusting for identified confounders, the incidence of cataract was higher in statin users in comparison with nonusers (odds ratio, 1.27; 95% CI, 1.15-1.40). Sensitivity analysis confirmed this relationship. CONCLUSIONS AND RELEVANCE The risk for cataract is increased among statin users as compared with nonusers. The risk-benefit ratio of statin use, specifically for primary prevention, should be carefully weighed, and further studies are warranted.

Emergence of community-acquired methicillin-resistant Staphylococcus aureus skin and soft tissue infections as a common cause of hospitalization in United States children

BACKGROUND Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) was first observed in pediatric patients in the late 1990s. Since then, possible risk factors for contracting CA-MRSA have been hypothesized, but supporting studies are limited. METHODS We analyzed hospital discharge records for patients with a principal International Classification of Diseases, Ninth Revision code for skin and soft tissue infections, collected from 1996 to 2006 by the United States National Center for Health Statistics. Noninstitutional, short-stay hospitals in the United States participated. The sample was limited to patients aged ≤19 years. Staphylococcus aureus and CA-MRSA were defined by International Classification of Diseases, Ninth Revision codes. Data weights were used to derive regional and national estimates. Population estimates were obtained from the US Bureau of the Census, and incidence rates were reported per 100,000 persons. Risk factors for CA-MRSA were first identified using χ(2) and χ(2) goodness-of-fit tests, then by multivariable logistic regression. RESULTS These data represent 616,375 pediatric discharges for skin and soft tissue infections from U.S. hospitals between 1996 and 2006. This represents approximately 69.9 hospitalizations for skin and soft tissue infections per 100,000 U.S. children per year. Staphylococcus aureus and CA-MRSA accounted for 19.6% and 9.6% of these cases, respectively. The rate of hospitalization for CA-MRSA skin and soft tissue infections increased dramatically over the study period; from less than one case per 100,000 in 1996 to 25.5 cases per 100,000 in 2006. Rates of CA-MRSA varied by region, with the South region having the highest rate (11.5 per 100,000 US children), followed by the West (5.2), Northeast (3.4), and Midwest (3.2). Peak CA-MRSA incidence occurred from May to December; however, the incidence in the South region was consistently higher than other regions for most months and the period of peak incidence was longer than other regions. Independent risk factors for CA-MRSA included survey year, race, geographic region, hospital size, and health insurance status (P < .0001 for all risk factors). CONCLUSIONS Pediatric hospitalizations for methicillin-susceptible S. aureus and CA-MRSA skin and soft tissue infections are on the rise. Possible risk factors for CA-MRSA infection include White race, residence in the South region of the United States, and lack of health insurance.

Disparities in the Use of Chemotherapy and Monoclonal Antibody Therapy for Elderly Advanced Colorectal Cancer Patients in the Community Oncology Setting

BACKGROUND The clinical trials on which the treatment of advanced colorectal (CRC) is based enroll few elderly patients. Furthermore, few investigations have determined the use and outcomes of the treatment of advanced CRC in practice. This study evaluated the treatment of advanced CRC in community oncology practices, focusing on age-related differences in treatment and outcome. METHODS A national, retrospective chart review was conducted to evaluate the management of advanced CRC in 10 community practices across the U.S. All medical records of patients diagnosed with advanced CRC initiating chemotherapy treatment after January 1, 2003 through 2006 were included. The primary aim was to compare the proportion receiving doublet chemotherapy (irinotecan or oxaliplatin with a fluoropyrimidine) as initial therapy in young (age <or=65 years) and elderly (age >65 years) patients. Additional aims included age-based comparisons of the addition of bevacizumab to chemotherapy, overall chemotherapy use, all-cause mortality, and toxicity-related events. RESULTS Overall, 520 patients (56% elderly) received 6,253 cycles of chemotherapy. Of the younger patients, 84% received doublet chemotherapy first-line, compared with 58% of elderly patients (p < .001). The use of each of the medications--irinotecan, oxaliplatin, and bevacizumab--was lower in elderly patients (p < .001). Independent predictors of a higher risk for mortality were age >65 (adjusted hazards ratio [HR],1.19; 95% confidence interval [CI], 1.02-1.39) and performance status score >or=2 (HR, 1.65; 95% CI, 1.41-1.91). CONCLUSION Elderly patients are less likely to receive first-line doublet chemotherapy than younger patients. Age and performance status are independent predictors of treatment and overall survival.

Trimethoprim-Sulfamethoxazole or Clindamycin for Community-Associated MRSA (CA-MRSA) Skin Infections

Background: In the United States, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as the predominant cause of skin infections. Trimethoprim-sulfamethoxazole (TMP-SMX) and clindamycin are often used as first-line treatment options, but clinical data are lacking. Methods: We conducted a retrospective cohort study of outpatients with skin and soft tissue infections managed from July 1 to December 31, 2006. Patients younger than 18 years of age were excluded, as were those who had no clinical admission or progress notes; were hospitalized within the 90 days before admission; were hospitalized with polymicrobial, surgical site, catheter-related, or diabetic foot infections; or were discharged to places other than home. Patient demographics, comorbidities, diagnoses, cultures, prescribed antibiotics, susceptibilities, surgical procedures, and health outcomes were extracted from electronic medical records. Patients were divided in 2 cohorts for further analysis: TMP-SMX and clindamycin. The primary study outcome was composite failure defined as an additional positive MRSA culture from any site 5 to 90 days after treatment initiation or an additional intervention during a subsequent outpatient or inpatient visit. Baseline characteristics and failure rates were compared using χ2, Fishers exact, and Wilcoxon rank sum tests. Results: A total of 149 patients were included in this study. These patients had a median age of 36 years, 55% were men, 71% were Hispanic, 42% were uninsured, and 60% received an incision and drainage procedure. Patients who did not receive incision and drainage were twice as likely to experience the composite failure endpoint (57% vs 29%; P < .001). Failure rates were 25% for patients who received incision and drainage plus antibiotics compared with 60% for patients who received incision and drainage minus antibiotics (P = .03). When patients who did not receive incision and drainage were excluded, there were no significant differences between the TMP-SMX (n = 54) and clindamycin (n = 20) cohorts with respect to composite failures (26% vs 25%), microbiologic failures (13% vs 15%), additional inpatient interventions (6% vs 5%), or additional outpatient interventions (20% vs 20%). Conclusions: Our findings reinforce the belief that incision and drainage and antibiotics are critical for the management of CA-MRSA skin infections. Patients who receive TMP-SMX or clindamycin for their CA-MRSA skin infections experience similar rates of treatment failure.